There is substantial evidence that opioid analgesic use impairs immune system responses and there has been a long-standing concern that these effects increase the risk of serious, potentially life-threatening infections. In vivo studies in animal models and human subjects have demonstrated that opioids affect surrogate markers of immune functions that are crucial for prevention of serious infections, such as white cell migration and phagocytosis. Although studies have demonstrated significant dose-dependent suppression of immunological functions in animal models and humans as well as a dose-dependent increase in the risk of serious infections in animal models, the clinical relevance of these findings in humans remains unclear. These concerns are particularly relevant for older adults, who are commonly affected by pain and are at increased risk for infections. A number of opioid analgesics are currently available, but not all have the same immunosuppressive properties. Studies in animal models suggest that, taking the chemical structure of morphine as reference, opioids with hydroxyl groups at both C3 and C6 (e.g. morphine), have the strongest immunosuppressive effects, whereas modification at C3 alone (e.g. codeine) reduces immunosuppression, and substitution of a carbonyl group at C6 (e.g. hydromorphone) eliminates the immunosuppressive effects. Identifying those opioids that are the least likely to increase the risk of serious infections will be crucial to inform the selection of analgesics for vulnerable older adults. Furthermore, the immunosuppressive effects of opioids are dose-dependent and for several opioids, in vivo data suggest that concurrent use of opioids and other commonly used medications that inhibit opioid metabolism could markedly increase the serum concentration of opioids. We propose to conduct a series of studies of older adults with the following specific aims: 1) Test the hypothesis that the risk of serious infections in new users of codeine (which is metabolized to morphine) is greater than in new users of other opioids with comparable analgesic properties; 2) Test the hypothesis that the risk of serious infections in new users of morphine is greater than in new users of other opioids with comparable analgesic properties; and, 3) Test the hypothesis that concurrent use of oxycodone or methadone and strong inhibitors of their metabolism increases the risk of serious infections relative to such use without metabolic inhibitors. The proposed studies will use a retrospective cohort study design and data from Tennessee Medicaid, to compare the incidence of serious infections associated with the use of selected opioids while controlling for the effect of relevant baseline and time-varying covariates. Our research team has the combination of experience and expertise needed to successfully complete the proposed projects. The proposed studies are designed to have a high impact on the field of pain therapeutics, advance our understanding of the effects of opioid analgesics on the risk of serious infections and inform the clinical care of older adults.